PARP Inhibitor - Lynparza Effective in Men with BRCA-Mutant Prostate Cancer

Men with prostate cancer have genomic defects that can be targeted with Lynparza and should undergo genomic testing.

by Dr. C.H. Weaver M.D. updated 8/2019

Precision cancer medicines known as PARP Inhibitors are increasingly used to treat women with ovarian or breast cancer with specific genomic defects that prevent them from repairing DNA which results in cancer. Approximately 1 in 4 men with prostate cancer appear to have similar defects in DNA repair and can benefit from treatment with a PARP Inhibitor.

The PARP Inhibitor Lynparza has been demonstrated to delay the progression of prostate cancer in men with refractory cancer.

About Lynparza (olaparib)

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first precision cancer medicine to block DNA damage response (DDR) in cancers harbouring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2.

The PARP enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Precision cancer medicines that target and inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy and are called PARP inhibitors. By blocking this enzyme, DNA inside the cancerous cells is less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth.

Lynparza was the world’s first drug to reach the market targeted against inherited cancer mutations, and was found to benefit as many as a third of patients with prostate cancer, including many who did not inherit cancer genes but whose cancers had acquired defects in DNA repair according to initial study results released in the New England Journal of Medicine in 2015.

In that trial, 49 men with treatment-resistant, advanced prostate cancer received Lynparza, and 16 of them (33%) responded, as defined by a set of clinical criteria. Lynparza stopped prostate cancer growth, generating lasting falls in prostate specific antigen (PSA) levels, falls in circulating cancer cell counts in the blood, and radiological responses on CT scans and MRI.

The clinical trial found that up to 30% of men with advanced prostate cancer with defects in their systems for repairing DNA detected by genomic testing – and that these responded particularly well to Lynparza.

The results of the trial led to the TOPARP-B clinical trial in which only men whose prostate cancers had detectable DNA repair mutations were treated with Lynparza. All men enrolled in the trial had advanced diseased that had progressed on androgen deprivation therapy, 99% had received Taxotere, 90% Zytiga, Xtandi, and 38% Jevtana.

The overall response rate to treatment was 54% in 98 men with DNA repair mutations. Among 30 men with confirmed mutations in BRCA 1/2 alterations, 83.3% responded to treatment, and 57.1% with PALB2 alterations responded to the treatment. Lynparza delayed cancer progression an average of 5.5 months

The PROfound Clinical Trial in Castrate Resistant Prostate Cancer

The PROfound clinical trial evaluated the effectiveness and safety of Lynparza compared with enzalutamide or abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on prior treatment with new hormonal anticancer treatments and had a qualifying genetic mutation in one of 15 genes involved in the HRR pathway, including among BRCA1/2, ATM and CDK12.(3)

Results from the trial showed that Lynparza delayed cancer progression compared to enzalutamide or abiraterone in men with mCRPC selected for BRCA1/2 or ATM gene mutations, a subpopulation of HRR gene mutations and further confirm the value of performing genomic testing in men with advanced prostate cancer.

The researchers have reported that 27 per cent of men with refractory prostate cancer have alterations in one or more genes linked to repairing damaged DNA. BRCA mutations are by far the most common and were found in 33 per cent of the cancers with a DNA repair mutation. Other common DNA repair mutations were the genes ATM, CDK12, CHEK2 and PALB2.

References:

  1. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. The New England Journal of Medicine. 373:1697-1708. October 29, 2015,
  2. https://abstracts.asco.org/239/AbstView_239_254043.html
  3. https://www.astrazeneca.com/media-centre/press-releases/2019/lynparza-phase-iii-profound-trial-in-hrr-mutation-selected-metastatic-castration-resistant-prostate-cancer-met-primary-endpoint-07082019.html
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